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Biomedical subjects

H Lage

Publications and source records attributed to H Lage.

At least 37 records · Page 2Linked to original sources
PubMed1999

Involvement of the DNA mismatch repair system in antineoplastic drug resistance.

Different types of antineoplastic drugs, such as the alkylating agents busulfan, N-methyl-N'-nitro-N-nitrosoguanidine, N-methyl-N-nitrosourea, procarbazine and temozolomide, the antimetabolites, mercaptopurine and 6-thioguanine, the platinum compounds carboplatin and cisplatin, the anthracycline doxorubicin and the epipodophyllotoxine etoposide act by damaging DNA directly or indirectly. Increasing evidence has shown that tumours could acquire resistance to these drugs by loss of DNA-mismatch repair (MMR) activity. This phenomenon is caused by a decreased MMR-dependent stimulation of signal-transduction pathways causing programmed cell death. Simultaneously, the mutation rate in MMR-deficient tumours is increasing, which could lead to additional secondary drug/resistance phenotypes to other antineoplastic agents. In addition to this, an enhanced mutation rate may contribute to increased phenotypic variation and therefore the clinical aggressiveness of primary tumours and their metastases.

Animals↗
PubMed1998

Increased expression of annexin I and thioredoxin detected by two-dimensional gel electrophoresis of drug resistant human stomach cancer cells.

The therapy of advanced cancer using chemotherapy alone or in combination with radiation or hyperthermia yields an overall response rate of about 20-50%. This success is often marred by the development of resistance to cytostatic drugs. Our aim was to study the global analysis of protein expression in the development of chemoresistance in vitro. We therefore used a cell culture model derived from the gastric carcinoma cell line EPG 85-257P. A classical multidrug-resistant subline EPG85-257RDB selected to daunorubicin and an atypical multidrug-resistant cell variant EPG85-257RNOV selected to mitoxantrone, were analysed using two-dimensional electrophoresis in immobilized pH-gradients (pH 4.0-8.0) in the first dimension and linear polyacrylamide gels (12%) in the second dimension. After staining with coomassie brilliant blue, image analysis was performed using the PDQuest system. Spots of interest were isolated using preparative two-dimensional electrophoresis and subjected to microsequencing. A total of 241 spots from the EPG85-257RDB-standard and 289 spots from the EPG85-257RNOV-standard could be matched to the EPG85-257P-standard. Microsequencing after enzymatic hydrolysis in gel, mass spectrometric data and sequencing of the peptides after their fractionation using microbore HPLC identified that two proteins annexin I and thioredoxin were overexpressed in chemoresistant cell lines. Annexin I was present in both the classical and the atypical multidrug-resistant cells. Thioredoxin was found to be overexpressed only in the atypical multidrug-resistant cell line.

Annexin A1↗
PubMed1998

Chromosome alterations in breast carcinomas: frequent involvement of DNA losses including chromosomes 4q and 21q.

Comparative genomic hybridization was applied to map DNA gains and losses in 39 invasive ductal breast carcinomas. Frequent abnormalities included gains on chromosomal regions 1q, 8q, 11q12-13, 16p, 19, 20q and X as well as frequent losses on 1p, 5q, 6q, 9p, 11q, 13q and 16q. Furthermore, frequent losses on 4q (20 cases) and 21q (14 cases) were found for the first time in this tumour type. High copy number amplifications were observed at 8q12-24, 11q11-13 and 20q13-ter. Highly differentiated tumours were associated with gains on 1q and 11q12-13 along with losses on 1p21-22, 4q, 13q, 11q21-ter. Undifferentiated breast carcinomas were characterized by additional DNA imbalances, i.e. deletions of 5q13-23, all of chromosome 9, the centromeric part of chromosome 13 including band 13q14 and the overrepresentation of chromosome X. We speculate that these changes are associated with tumour progression of invasive ductal breast cancer.

Breast Neoplasms↗
PubMed1998

Expression of the novel mitoxantrone resistance associated gene MXR7 in colorectal malignancies.

It was shown previously that a glypican encoding gene (MXR7/GPC3/OCl-5) was associated with mitoxantrone resistance in vitro. This study describes and investigation of an association between multidrug resistance and MXR7 in surgical cryo-specimens of 51 gastrointestinal tumors. The mRNA expression levels differ widely according to tumor species. In primary colorectal cancers, the level of MXR7 mRNA expression correlated loosely with the mRNA expression level of the multidrug-resistance-associated protein (MRP). In colorectal metastases an elevated MXR7 mRNkA expression level was observed when compared to primary colorectal carcinomas.

ATP-Binding Cassette Transporters↗
PubMed1997

Decreased drug accumulation in a mitoxantrone-resistant gastric carcinoma cell line in the absence of P-glycoprotein.

An established gastric-carcinoma cell line, EPG85-257P, is extremely sensitive to mitoxantrone (IC50, 0.12 ng/ml). Stepwise selection with mitoxantrone for 3 years resulted in a cell line (EPG85-257RN) that is 7,056-fold resistant to mitoxantrone (IC50, 846 ng/ml) and displays cross-resistance to the topoisomerase(topo)-II poisons ametantrone (411x), etoposide (112x) and teniposide (60x) as well as the topo-I poisons 7-ethyl-10-hydroxycamptothecin (331x) and topotecan (58x). We now show that this resistance is multifactorial. Western blotting revealed a 5-fold decrease in topo-IIalpha polypeptide in the mitoxantrone-resistant cells. Immunohistochemistry and Western blotting failed to demonstrate P-glycoprotein overexpression. Formation of trapped topo-II-DNA complexes in the resistant cells required higher mitoxantrone concentrations than in parental cells, even though nuclei isolated from the EPG85-257RN cells formed cleavage complexes normally. In agreement with these observations, which suggest the possibility of a defect in mitoxantrone accumulation, examination of mitoxantrone accumulation in both cell lines by confocal laser microscopy revealed that the EPG85-257RN cells accumulate less mitoxantrone at steady state. From these results, we propose that mitoxantrone accumulation, along with alterations in topo-IIalpha expression, contribute to the resistance to mitoxantrone observed in these cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Cloning and characterization of human cDNAs encoding a protein with high homology to rat intestinal development protein OCI-5.

We constructed a lambda complementary DNA expression library from the mitoxantrone-resistant human gastric carcinoma cell line EPG85-257RNOV. The library was screened by differential hybridization (resistant cell line against non-resistant cell variant). By this procedure we found five independent cDNA clones representing one single gene that has much higher expression in the mitoxantrone-resistant cell line EPG85-257RNOV than in the non-resistant variant EPG85-257P. One of the cDNA clones (MXR7) contains a complete open reading frame (ORF) encoding a 580-amino acid polypeptide. Amino acid and nucleotide sequence analysis revealed that this gene codes the human variant of a rat intestinal development protein OCI-5.

Amino Acid Sequence↗
PubMed1996

Cloning of a human cDNA encoding a protein with high homology to yeast methionyl-tRNA synthetase.

A composite 2779-bp cDNA that encodes human cytoplasmic methionyl-tRNA synthetase (MetRS) has been constructed from partial cDNA clones derived from the gastric carcinoma cell line EPG85-257RNOV and the nucleotide sequence has been determined. The open reading frame (ORF) encodes a 900 amino acid (aa) protein with a predicted molecular mass of 101 kDa. Northern blotting analysis of total RNA extracted from human gastric carcinoma cells demonstrated a single band with a mobility corresponding to a size of 3.0 kb.

Amino Acid Sequence↗